PROJECT SUMMARY/ABSTRACT Chemotherapy-related cognitive impairment (CRCI) is associated with reduced quality of life and survival making it a significant problem that remains understudied. Research by our group and others has demonstrated that CRCI is associated with altered brain structure and function from pretreatment to post treatment. There is significant overlap between chemotherapy actions and physiologic processes involved in aging. Neurocognitive have been found in patients up to 20+ years post- treatment and work by our group and others suggests an accelerated brain aging phenotype in breast cancer survivors treated with chemotherapy. We have also observed that patients may demonstrate unique trajectories of cognitive impairment that require further study. Existing prospective, longitudinal studies of cancer and cognition, including our own, have been limited to relatively short-term post- treatment follow-ups (e.g. 6-12 months). To begin addressing these limitations, we aim to extend our current prospective study (CA172145), which longitudinally examines cognitive function and brain structure/function pre-surgery, 1-month post chemotherapy, and 1-year post chemotherapy. We will continue to assess cohorts of women treated with chemotherapy, chemotherapy nave patients, and healthy controls at yearly intervals for 5 additional years (up to 10 years). Using non-invasive neuroimaging methods, we will advance our original aims from the initial project to measure very long- term neurobiologic outcomes with an emphasis on the assessment of neural connectivity rather than specific regional changes (Aim 1). We will also examine very long-term cognitive outcomes as measured by standardized neuropsychological testing (Aim 2). Finally, we will explore different trajectories or subtypes of impairment and their neural phenotypes (Aim 3). The proposed project will significantly advance the understanding of chemotherapy-related cognitive impairments by extending our knowledge on very long-term neurobiological outcomes along with the different subtypes of cognitive impairments and associated neural profiles following breast cancer chemotherapy.